Antigen Express scientists have discovered that a segment of the Ii protein called Ii-Key, which acts at an allosteric site on one end of the antigenic peptide binding site on MHC Class II molecules, greatly enhances the binding of a tethered epitope. Linkage of such Ii-Key with a MHC class II-restricted epitope in a hybrid enhances the potency of presentation of the epitope >200 times, in vitro with murine and human assays, inducing a TH1 pattern of cytokine release. We propose to test such compounds with HIV MHC class II-restricted epitopes to expand CD4+ immunity and memory toward enhancing efficacy of HIV CTL peptide vaccines, the safest approach to HIV vaccination. We will: 1) design and synthesize several Ii-Key/HIV class II epitope hybrids according to our established methods; 2) test in mice the potencies of these hybrids in terms of T helper cell proliferation and the induction of neutralizing antibody against class II-restricted HIV epitope; and 3) design and synthesize an Ii-Key/class II epitope/CTL epitope double hybrid according to the data of 2); and then test the vaccine efficacy of this double hybrid in CTL induction. Our experiments will lead to a very potent HIV peptide vaccine. In a Phase II program the efficacy of such hybrids will be tested in higher primates and man. PROPOSED COMMERCIAL APPLICATION: Ii-Key/HIV peptide vaccine strategy will result in a very potent HIV peptide vaccine, the safest HIV vaccine. This entirely synthetic vaccine can be manufactured in a large scale and be given to those at high risk of HIV infection.